Enhanced effect of two drugs when given together, vs. each drug by itself.

Marked by FOURFOLD or greater REDUCTION in MIC of each drug when used in combination vs. when used alone. (dec. MIC, INC. Potency)

FIC <0.5

What is Antagonism?

Combined INHIBATORY or killing effects of two or more drug. Effects are significantly LESS than expected with used together vs. when used alone.

FIC >4

What is Indifference?

COMBINED inhibitory or killing effect is the same when used together or alone.

FIC between 0.5 and 4 (0.5 <x>4)

What is FIC?

Fractional Inhibitory Concentration Index

FIC index = FICa + FICb

FICa=MIC drug a in combination

MIC drug a alone

FICb=MIC drug b in combination

MIC drug b alone

What are the FIC values:

Synergism: <0.5

Antagonism: >4

Indifference: between 0.5 and 4

What are the Mechanisms of SYNERGISTIC actions?

1. Blockage of sequential Steps in a metabolic pathway (combination antibiotic with 1 antibiotic inhibiting a step in a pathway, and the 2nd antibiotic inhibiting the next right after in the SAME pathway)

4. Binding of ONE antibiotic ENHANCES the binding of another antibiotic (Senersid: binding of first drug enhances binding of second drug)

What are the mechanisms of ANTAGONISTIC actions?

1. Inhibition of CIDAL drugs by STATIC drugs (static drugs stop cell division, but many cidal drugs need the cell to divide in order for it to work.) BUT keep in mind the MECHANISM OF ACTION of static/cidal drugs. ex: tetracyclines (static) and aminoglycosides (cidal), but they are INDEFERENT.

2. Induction of enzymatic inactivation. ex: some antibiotics induce production of certain bacterial enzymes that may inactivate the second antibiotic. ex: Penicillin (B-lactam) and Imipenem (induces B-lactamases)

What are some problems with Microbial Resistance?

-resistance is an increasingly important public health concern and factor in ALL hospital-acquired (nosocomial) infections and community acquired infections.

-Microbial resistance is EVOLUIONARY.

-Rapid emergence and dissemination of MDR strains.

What are some Contributing Factors to Microbial Resistance?

1. Microbes ADAPT quickly to new environments

2. Microbes have SMALL number of genes, and single random gene mutations can have large impact on properties

3. Microbes replicate fast, and evolve fast

4. A mutation that helps a microbe survive can quickly become predominate throughout population

5. Microbes can get genes, including resistant genes, by direct transfer from their own species and from other species

6. Widespread and Inappropriate use of antibiotic theraypy (antibiotic use for viral infections, improper dosage, lack of bacterial information on organism, use of antibiotic in animal feed, antibiotics as OTC products in other parts of the world)

7. Patient NONCOMPLIANCE

Why is it relevant to the U.S. that antibiotics can be OTC in other parts of the world?

Some people order their drugs from out of the country, and microbes can be easily transfered with international travels.

What are the mechanisms of Microbial Resistance?

1. Drug inactivation by enzymes- bacteria can make enzyme that inactivates the antibiotic

2. Target Modification (chromosomal mutation)- result of spontaneous mutation on chromosome, leading to ability of bacteria to change chemistry of the "binding site" for the antibiotic.

3. COnjugation -mating between bacterial cells (between species or non species can occur)*the most important mechanism that contribut to resistance

4. Transposition - transfer of R Factor when the gene is located on "transposons" (jumping genes- change locations) R Factor will jump and be incorporated in choromosmes leading to Chromosomal resistance